In the Central Nervous System (CNS), Gram-positive bacterial infections represent about 50% of the bacterial diseases and are often associated with high mortality and severe permanent neurological consequences. The major immunostimulatory principles of Gram-positive bacteria are the constituents of bacterial cell walls, lipoteichoic acid (LTA) and peptidoglycan (PGN). In contrast to lipopolysaccharide (LPS) from Gram-negative bacteria, the role and the mechanisms of Gram-positive bacterial components in inducing inflammation in the CNS are still poorly understood.
The aim of the present Ph.D. thesis was to characterize which type of cells is involved in the inflammatory response of the CNS induced by LTA isolated from Staphylococcus aureus and/or muramyl dipeptide (MDP, the smallest active fragment of peptidoglycan).
Since inflammation in the CNS is mainly mediated by activated glia, in the first part of the thesis, the inflammatory potential of lipoteichoic acid (LTA) (in the presence and absence of
MDP) was studied using primary cultures of astrocytes or microglia. Furthermore, the extra- and intracellular pathways involved in LTA-signalling were investigated, with emphasis on the role of Toll-like receptors (-2 and -4) and mitogen-activated protein kinases (MAPK), p38 and ERK1/2. In the second part of the studies, the mechanisms of neuronal cell death induced by lipoteichoic acid (LTA) and muramyl dipeptide (MDP) were investigated using primary culture of rat cerebellar granule cells (CGCs).
The obtained results indicate that LTA-induced inflammation in the CNS is mediated by activated astrocytes and microglia. LTA-activated glial cell can cause neuronal cell death that is mediated by oxidative and nitrosative stress as well as caspase activation. These results suggest that pharmacological control of glia activation (blockage of Toll-like receptor-2 and the inhibition of MAPK signalling pathway) and the control of oxidative and nitrosative stress or caspase activation could provide the basis of a potential, novel adjunctive therapy of Gram-positive bacterial infections in the CNS.